Dr. W. Davis Parker Jr., the Eugene P. Meyer Professor of
the Neurosciences, remembers the events that led to his
pursuit of scientific truth: the place where
the magnum opus he is still composing all began.
While a student at the University of South Florida College of Medicine, Parker
developed an interest in metabolic diseases, which interfere with the biochemical
process of turning nutrients into energy at the cellular level. As part of
his clinical training, he took care of children with Reye’s Syndrome, a deadly
but relatively rare metabolic disease affecting the liver and brain.

One day in 1974, late in his senior year, Parker came across
a journal article. It described a newly discovered metabolic
problem called Carnitine Deficiency,
which sounded suspiciously like Reye’s Syndrome.

A few weeks into Parker’s internship in medicine and pediatrics at University
of South Florida Affiliated Hospitals, another child with Reye’s Syndrome
was admitted. Parker examined the child and ran some tests. Sure enough, the
child’s concentrations of carnitine, an essential amino acid, were well
below normal.

The
child “made the third case of Carnitine Deficiency ever
described,” Parker
said, and the discovery, reported in Pediatric Research in 1976, ave
Parker his first journal byline.

It was a pivotal moment in Parker’s career. A metabolic problem — a
biochemical defect — had been shown to underlie Reye’s Syndrome. “And
it was totally mitochondrial,” Parker said.

Which, according to established views, was also totally impossible.
Mitochondria are the energy-producing structures within cells, and they are essential
for life. Therefore, scientists believed that defective mitochondria
could
only lead
to death, not
disease. Parker now believed otherwise.

After conducting residencies in pediatrics at the University of
South Florida and then pediatric neurology at the University
of Virginia,
Parker headed
to the University of Colorado School of Medicine. There, he had
the freedom to
contemplate mitochondrial DNA in earnest.

Parker developed three important theories: One, he could study
brain disease at the metabolic level by using fresh, intact
mitochondria drawn from blood
platelets. Two, mitochondrial DNA, which is inherited only
from the
mother, might be the
cause of neurodegenerative diseases that appear to occur sporadically,
or randomly, instead of in a predictable pattern, as do diseases
involving chromosomal
DNA
inherited from both parents. Three, the lifelong replication
of mitochondrial genes could explain why some sporadic diseases,
like
Parkinson’s, are typically
late-onset. If abnormal mitochondrial genes replicated at a faster rate than
healthy ones, then late-onset diseases might be catalyzed by the abnormal genes
having reached a particular level of abundance.

“
He was thinking about all of this way before anything of this sort was being
written about or talked about,” said Janice K. Parks, his lab partner.

Using his platelet technique, Parker began to study the mitochondria
of patients with Leber’s Hereditary Optic Neuropathy, which is inherited through the
mother and causes blindness.

These studies allowed Parker to “conclude that mitochondrial diseases,
for whatever reason, can be both systemic and extremely focal,” he said.

And if one mitochondrial disease could knock off the
optic nerve and produce Leber’s, “why couldn’t there be another mitochondrial disease
that knocks off the substantia nigra, in which case you’ve got Parkinson’s?” Parker
speculated.

Unfortunately, “this type of mutation was thought not to exist,” Parker
said.

Back in the late 1980s, scientists investigating
sporadic neurodegenerative diseases believed the
diseases were
caused by toxins or traumas,
maybe even nutritional
imbalances, but not by genetic error. Additionally,
disease investigators rarely talked across pathological
boundaries.
Not everyone appreciated
Parker’s
describing biochemical problems suggesting that individual diseases were, in
fact, “absolute kissing cousins,” he said.

Parker was entering “dangerous territory,” Parks said.

The professional hazards didn’t deter Parker, although they were “kind
of nerve-wracking,” he admitted. Yet, he pressed forward.

“I
was used to criticism,” he said. “Besides, for the life of me,
I couldn’t see what the big deal was. If I was wrong, I was wrong. An awful
lot of research is ultimately either wrong, or it becomes a subset of somebody
else’s research. One of the things I love about science is that the truth
is what the truth is. Nothing can change that.”

Parker then developed an innovative laboratory
technique which proved that the defects
were genetically based,
and not the
result of exposure
to toxins,
as
many scientists still conjectured.

Despite the big media splash this discovery
made, Parker’s victory in the “gene-versus-toxin” debate
was qualified. The medical research
community now demanded that he show them the abnormalities.

“That
sounds like about two weeks of work, but it ain’t,” Parker said. “If
you’re looking at a chromosomal gene to see whether it causes, say, sickle
cell anemia, you’ve only got three choices: either both genes work, or
only one works, or neither of them work,” Parker said. “It’s
pretty easy to figure that out by
sequencing the chromosomal DNA.”

But what about an adult brain cell
that, by midlife, may contain
50,000 copies
of every
mitochondrial
gene? How
many of them
have to be defective,
or in
what combinations, before a genetic
disease occurs?
After a couple of years of daunting
technical endeavor, Parker is
now showing through
DNA sequencing that
mitochondrial genes are replete
with mutations. “In
fact, there are so many errors in the mitochondrial genes we’ve sequenced
that we’re having trouble figuring out what is relevant and what isn’t,” he
said.

Even so, despite a mounting pile
of evidence published in journals
and
replicated
by other scientists,
Parker still
runs into
the scientific stalwart who
wants to dismiss his hypothesis out
of hand. This doesn’t bother him
too much.

“You
can lead people to water, but you can’t make them think,” Parker
jested. “There is nothing you
can do except groan and move on.”

Undoubtedly, the patients
who stand most to gain
from Parker’s magnum opus
are happy about that, too. His research has enormous potential for the diagnosis,
treatment and cure of diseases caused by errors in mitochondrial DNA like Alzheimer’s,
Parkinson’s, ALS, schizophrenia
and autism.

“The
ultimate goal is that we can learn to make sick mitochondria better,” Parker
said. “And if we can’t do that, at least to freeze the progression
of a disease caused by sick mitochondria before you even know you’ve
got it.”